CsA is a member of a group of cyclic undecapeptides with anti-inflammatory, immunosuppressive, antifungal and antiparasitic properties. The immunomodulatory properties are of particular interest in medicine, since they are important in prevention of organ rejection in transplantation surgery and for autoimmune diseases.
Cyclosporins are a class of compounds which were first described in Swiss patents 589716 and 603790. They have been reviewed in the monograph by Borel [Cyclosporin, Progress in Allergy (1986) 38, Karger Press] discussing the chemical structure and the biological-pharmacological properties.
Over 20 different cyclosporins are produced by fungi all having varying amino acid composition. CsA is the major component and currently enjoys the most widespread clinical use.
In extensive screening experiments, numerous fungal species were found to have CsA forming properties. Dreyfuss [Sydowia (1986) 39, 22–36] described an exclusively Cyclosporin forming ability for Cylindrocarpon and Fusarium. Cyclosporin formation is also reported from following—Tolypocladium geodes, Trichoderma virile, Neocosmospora vasunfecta, Isaria spp., Verticillium spp., Acremonium spp. and Beauveria nivea. 
Sesquicilliopsis rosariensis F 605 with 3150 mg/L after 14 days of submerged fermentation and Tolypocladium inflatum Wb 6-5 with 1100 mg/L after 11 days of fermentation are known to be high producers (U.S. Pat. No. 5,256,547, 1993). Tolypocladium inflatum KD 461, a mutant when supplemented with L-leucine and L-valine produced 8920 mg/L after 13 days (WO Patent No. 96/12032, 1996).
Tolypocladium inflatum strains have been used in solid state fermentation for Cyclosporin fermentations. Strains producing 1.95 g/kg to 4.84 g/kg of wheat bran during 5–10 days of fermentation have been reported [Balaraman and Mathew EP No. 0 725 076 (1996); Sekar and Balaraman, Ind. J. Microbiol. (1996) 36, 231–234; Sekar et al, Bioprocess Engg. (1997) 18, 257–259; Murthy et al, Process Biochem. (1999) 34, 269–280].
The economics of using a producing strain, the described volume-time-yields in the above process are not satisfactory. Further, there are difficulties of maintaining a low temperature of 25° C. There are also disadvantages in isolation and purification of different cyclosporins in this process.
The patent specification EP 0 725 076, also discloses a process for the manufacture of CsA by solid state fermentation—but uses a Tolypocadium sp. and an uncontained system. Since the fermentation process disclosed in EP 0725 076 is not contained it doesn't assure full safety for the cytotoxic fermentation products like CsA—making the process industrially unattractive.
The purification processes to isolate pharmacopoeial grade CsA used conventionally are extraction of fermented biomass using an organic solvent, evaporation of solvent, reextraction of residue, concentration and then subjecting the residue to various chromatographic processes to separate CsA from other cyclosporins and impurities viz., gel filtration typically LH-20 (U.S. Pat. Nos. 4,117,118 and 5,256,547) and/or silica gel or alumina columns (U.S. Pat. No. 4,117,118) or adsorption resin columns (patent No. WO 97/46575). Final yields obtained from the conventional processes are typically in the range of 40% to 60%. Removal of the lipids from the fermented media is done by using pet ether, hexane, acetone, methanol or a mixture of these (British patent No.GB 2,227,489). CsA being mixable in these lipids as well as in the mixture of acetone and petroleum ether, a significant amount of CsA is lost during this step.
Super critical fluid extraction has also been reported to have been used for separation of cyclosporin using super critical carbon dioxide (Canadian patent No. CA 2,108,655). This process has economic limitations for its commercial application.